Relevance of DNA Repair to Carcinogenesis and Cancer Therapy

  • M. F. Rajewsky
  • J. Engelbergs
  • J. Thomale
  • T. Schweer
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 154)

Abstract

DNA-reactive carcinogens and anticancer drugs induce many structurally distinct cytotoxic and potentially mutagenic DNA lesions. The capability of normal and malignant cells to recognize and repair different DNA lesions is an important variable influencing the risk of mutation and cancer as well as therapy resistance. Using monoclonal antibody-based immunoanalytical assays, very low amounts of defined carcinogen-DNA adducts can be quantified in bulk genomic DNA, individual genes, and in the nuclear DNA of single cells. The kinetics of DNA repair can thus be measured in a lesion-, gene-, and cell type-specific manner, and the DNA repair profiles of malignant cells can be monitored in individual patients. Even structurally very similar DNA lesions may be repaired with extremely different efficiency. The miscoding DNA alkylation products O6-methylguanine (O6-MeGua) and O6-ethylguanine (O6-EtGua), for example, differ only by one CH2 group. These lesions are formed in DNA upon exposure to N-methyl-N-nitrosourea (MeNU) or N-ethyl-N-nitrosourea (EtNU), both of which induce mammary adenocarcinomas in female rats at high yield. Unrepaired O6-alkylguanines cause transition mutations via mispairing during DNA replication. O6-MeGua is repaired at a similar slow rate in transcribed (H-ras,β- actin) and inactive genes (IgE heavy chain; bulk DNA) of the target mammary epithelia (which express the repair protein O6-alkylguanine-DNA alkyltransferase at a very low level). O6-EtGua, however, via an alkyltransferase-independent mechanism, is excised ~20 times faster than O6-MeGua from the transcribed genes selectively. Correspondingly, G:C → A:T transitions arising from unrepaired O6-MeGua at the second nucleotide of codon 12 (GGA) of the H-ras gene are frequently found in MeNU-induced mammary tumors, but are absent in their EtNU-induced counterparts.

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Copyright information

© Springer-Verlag Berlin · Heidelberg 1998

Authors and Affiliations

  • M. F. Rajewsky
    • 1
  • J. Engelbergs
    • 1
  • J. Thomale
    • 1
  • T. Schweer
    • 1
  1. 1.Institute of Cell Biology (Cancer Research) [IFZ]University of Essen Medical School and West German Cancer Center EssenEssenGermany

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